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Haematopoiesis, or the process of formation of mature blood cells from committed progenitors, represents an accessible and well-studied paradigm of cell differentiation and lineage specification. Genetic association studies provide a powerful approach to discover new genes, biological pathways and mechanisms underlying haematopoietic development. Here, we highlight recent findings of genomewide association studies (GWAS) linking 145 genomic loci to traits affecting the formation of red and white cells and platelets in European and other ancestries. We present strategies to address the main challenges in GWAS discoveries, particularly to find functional and regulatory effects of genetic variants, and to identify genes through which these genetic variants affect haematological phenotypes. We argue that studies of haematological trait variation provide an ideal paradigm for understanding the function of GWAS-associated variants owing to the accessible nature of cells, simple cellular phenotype and focused efforts to characterize the genetic and epigenetic factors influencing the regulatory landscape in highly pure mature cell populations.
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UNLABELLED: As new methods for multivariate analysis of genome wide association studies become available, it is important to be able to combine results from different cohorts in a meta-analysis. The R package MultiMeta provides an implementation of the inverse-variance-based method for meta-analysis, generalized to an n-dimensional setting. AVAILABILITY AND IMPLEMENTATION: The R package MultiMeta can be downloaded from CRAN. CONTACT: dragana.vuckovic@burlo.trieste.it; vi1@sanger.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Estudio de Asociación del Genoma Completo/métodos , Metaanálisis como Asunto , Programas Informáticos , Sitios Genéticos , Humanos , Análisis Multivariante , FenotipoAsunto(s)
Plaquetas/citología , Biología Computacional/métodos , Bases del Conocimiento , Megacariocitos/citología , Animales , Bases de Datos Factuales , Humanos , Cooperación Internacional , Internet , Modelos Biológicos , Fosforilación , Unión Proteica , Programas Informáticos , Interfaz Usuario-ComputadorRESUMEN
The authors use ideas from graph theory in order to determine how distant is a given biological network from being monotone. On the signed graph representing the system, the minimal number of sign inconsistencies (i.e. the distance to monotonicity) is shown to be equal to the minimal number of fundamental cycles having a negative sign. Suitable operations aiming at computing such a number are also proposed and shown to outperform all algorithms that are so far existing for this task. [Includes supplementary material].
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Algoritmos , Modelos Biológicos , Proteoma/metabolismo , Transducción de Señal/fisiología , Animales , Simulación por Computador , HumanosRESUMEN
AIMS/HYPOTHESIS: According to the thrifty genotype hypothesis, the high prevalence of type 2 diabetes and obesity is a consequence of genetic variants that have undergone positive selection during historical periods of erratic food supply. The recent expansion in the number of validated type 2 diabetes- and obesity-susceptibility loci, coupled with access to empirical data, enables us to look for evidence in support (or otherwise) of the thrifty genotype hypothesis using proven loci. METHODS: We employed a range of tests to obtain complementary views of the evidence for selection: we determined whether the risk allele at associated 'index' single-nucleotide polymorphisms is derived or ancestral, calculated the integrated haplotype score (iHS) and assessed the population differentiation statistic fixation index (F (ST)) for 17 type 2 diabetes and 13 obesity loci. RESULTS: We found no evidence for significant differences for the derived/ancestral allele test. None of the studied loci showed strong evidence for selection based on the iHS score. We find a high F (ST) for rs7901695 at TCF7L2, the largest type 2 diabetes effect size found to date. CONCLUSIONS/INTERPRETATION: Our results provide some evidence for selection at specific loci, but there are no consistent patterns of selection that provide conclusive confirmation of the thrifty genotype hypothesis. Discovery of more signals and more causal variants for type 2 diabetes and obesity is likely to allow more detailed examination of these issues.
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Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Genotipo , Obesidad/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Abastecimiento de Alimentos , Frecuencia de los Genes , Humanos , Modelos Genéticos , Obesidad/complicaciones , Obesidad/epidemiología , Polimorfismo de Nucleótido Simple , Prevalencia , Factores de Riesgo , Selección GenéticaRESUMEN
To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genome-wide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81x10(-5)). The C allele conferred a reduced risk of 33% to 41% using a case-control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA.
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Estudio de Asociación del Genoma Completo/métodos , Osteoartritis/genética , Proteínas de Unión al ARN/genética , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Mano , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Factores de Empalme de ARNRESUMEN
BACKGROUND: Telomere length is a predictor for a number of common age related diseases and is a heritable trait. METHODS AND RESULTS: To identify new loci associated with mean leukocyte telomere length we conducted a genome wide association study of 314,075 single nucleotide polymorphisms (SNPs) and validated the results in a second cohort (n for both cohorts combined = 2790). We identified two novel associated variants (rs2162440, p = 2.6 x 10(-6); and rs7235755, p = 5.5 x 10(-6)) on chromosome 18q12.2 in the same region as the VPS34/PIKC3C gene, which has been directly implicated in the pathway controlling telomere length variation in yeast. CONCLUSION: These results provide new insights into the pathways regulating telomere homeostasis in humans.
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Cromosomas Humanos Par 18 , Estudio de Asociación del Genoma Completo/métodos , Leucocitos/ultraestructura , Telómero/genética , Gemelos , Estudios de Cohortes , Interpretación Estadística de Datos , Femenino , Genoma Humano , Humanos , Leucocitos/metabolismo , Masculino , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados , Factores Sexuales , Telómero/química , Telómero/metabolismoRESUMEN
BACKGROUND: Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. METHODS AND RESULTS: We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11,550 cases and 11,205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81 x 10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44 x 10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02 x 10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34 x 10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P=0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86 x 10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. CONCLUSIONS: The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.
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Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Riesgo , Factores Sexuales , Población BlancaRESUMEN
BACKGROUND: Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density. METHODS: In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. FINDINGS: We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3.0x10(-6)). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2.3x10(-17)). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density. INTERPRETATION: Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.
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Densidad Ósea/genética , Fracturas Óseas/etiología , Proteínas Relacionadas con Receptor de LDL/genética , Osteoporosis/genética , Osteoprotegerina/genética , Polimorfismo de Nucleótido Simple/genética , Alelos , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 8 , Femenino , Expresión Génica , Marcadores Genéticos , Genoma Humano , Genotipo , Humanos , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad , Vértebras Lumbares , Masculino , Persona de Mediana Edad , Osteoporosis/complicacionesRESUMEN
Several lines of evidence suggest a role for the multidrug resistance gene (ABCB1/MDR1) and its product, P-glycoprotein 170, in the pathogenesis of inflammatory bowel disease (IBD). In addition, P-glycoprotein activity determines bioavailability of many drugs used regularly in many medical specialties, and ABCB/MDR1 variation appears to be a critical pharmacogenetic determinant. We have utilized a gene-wide haplotype tagging approach to further define the identity of germ-line variations in the ABCB1/MDR1 gene contributing to IBD susceptibility. Six haplotype tagging single nucleotide polymorphisms (tSNPs) representing the haplotypic variations of the ABCB1/MDR1 gene were identified initially following the characterization of the haplotype structure of this gene in 24 Centre d'Etude du Polymorphisme Humain Caucasian trios. Genotyping was performed in 249 ulcerative colitis (UC) and 179 Crohn's disease (CD) patients and 260 healthy controls. Using log-likelihood analysis, we observed a highly significant association between the common haplotypes and UC (P=4.22 x 10(-7)) but not CD (P=0.22). This significant association was critically dependent on one tSNP, intronic variant rs3789243. All haplotypes with this variant retained a highly significant association (P=3.2 x 10(-7)-3.6 x 10(-12)), whereas significance was lost when rs3789243 was dropped in systematic haplotypic analysis. The effect of this tSNP was independent of C3435T SNP, previously suggested to be the critical variant in disease susceptibility and drug transport. The association with UC was shown to be strongest with the phenotype of extensive disease (P=1.7 x 10(-7)). This 'candidate gene' approach provides compelling evidence to support the contribution of the ABCB1/MDR1 gene in determining risk to UC but not to CD and provides new insights into the localization of the critical susceptibility determinants within the gene. In addition, these findings have potentially important implications in the application of pharmacogenetics across a range of common diseases, including HIV, epilepsy and colorectal cancer.
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Colitis Ulcerosa/genética , Genes MDR , Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos , Fenotipo , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/fisiopatología , Enfermedad de Crohn/genética , Femenino , Humanos , Intrones , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Glutathione S-transferases (GSTs) comprise a large family of key defence enzymes against xenobiotic toxicity. Here we describe the comprehensive characterisation of this important multigene family in the model monocot species rice [ Oryza sativa(L.)]. Furthermore, we investigate the molecular evolution of the family based on the analysis of (1) the patterns of within-genome duplication, and (2) the phylogenetic relationships and evolutionary divergence among rice, Arabidopsis, maize and soybean GSTs. By in-silico screening of the EST and genome divisions of the Genbank/EMBL/DDBJ database we have isolated 59 putative genes and two pseudogenes, making this the largest plant GST family characterised to date. Of these, 38 (62%) are represented by genomic and EST sequences and 23 (38%) are known only from their genomic sequences. A preliminary survey of EST collections shows a large degree of variability in gene expression between different tissues and environmental conditions, with a small number of genes (13) accounting for 80% of all ESTs. Rice GSTs are organised in four main phylogenetic classes, with 91% of all rice genes belonging to the two plant-specific classes Tau (40 genes) and Phi (16 genes). Pairwise identity scores range between 17 and 98% for proteins of the same class, and 7 and 21% for interclass comparisons. Rapid evolution by gene duplication is suggested by the discovery of two large clusters of 7 and 23 closely related genes on chromosomes 1 and 10, respectively. A comparison of the complete GST families in two monocot and two dicot species suggests a monophyletic origin for all Theta and Zeta GSTs, and no more than three common ancestors for all Phi and Tau genes.
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Glutatión Transferasa/genética , Oryza/genética , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Evolución Molecular , Etiquetas de Secuencia Expresada , Duplicación de Gen , Expresión Génica , Genes de Plantas , Familia de Multigenes , Filogenia , Glycine max/genética , Zea mays/genéticaRESUMEN
Due to their maternal mode of inheritance, mitochondrial markers can be regarded as almost 'ideal' tools in evolutionary studies of conifer populations. In the present study, polymorphism was analysed at one mitochondrial intron (nad 1, exon B/C) in 23 native European Pinus sylvestris populations. In a preliminary screening for variation using a polymerase chain reaction-restriction fragment length polymorphism approach, two length variants were identified. By fully sequencing the 2.5 kb region, the observed length polymorphism was found to result from the insertion of a 31 bp sequence, with no other mutations observed within the intron. A set of primers was designed flanking the observed mutation, which identified a novel sequence-tagged-site mitochondrial marker for P. sylvestris. Analysis of 747 trees from the 23 populations using these primers revealed the occurrence of two distinct haplotypes in Europe. Within the Iberian Peninsula, the two haplotypes exhibited extensive population differentiation (PhiST = 0.59; P < or = 0.001) and a marked geographical structuring. In the populations of central and northern Europe, one haplotype largely predominated, with the second being found in only one individual of one population.
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Proteínas Mitocondriales , Secuencia de Bases , Cartilla de ADN/genética , ADN Mitocondrial/genética , ADN de Plantas/genética , Europa (Continente) , Evolución Molecular , Genes de Plantas , Marcadores Genéticos , Variación Genética , Haplotipos , Pinus sylvestris , Proteínas de Plantas/genética , Polimorfismo de Longitud del Fragmento de Restricción , Lugares Marcados de SecuenciaRESUMEN
We used chloroplast simple sequence repeats (cpSSRs) to examine whether there is any variation present in the chloroplast genome of Pinus torreyana (Parry ex Carrière) that may previously not have been detected using RFLPs. Analysis of 17 cpSSR loci showed no variation, which is consistent with previous cpRFLP work and confirms that the species is descended from an original, highly monomorphic population following a bottleneck. This lack of biological variation in the chloroplast genome of P. torreyana allowed us to estimate the mutation rates at cpSSR loci as between 3. 2 x 10(-5) and 7.9 x 10(-5). This estimate is lower than published mutation rates at nuclear SSR loci but higher than substitution rates elsewhere in the chloroplast genome.
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Cloroplastos/genética , ADN de Plantas/genética , Repeticiones de Microsatélite , Mutación , Árboles/genética , Cartilla de ADN , Marcadores Genéticos , Reacción en Cadena de la Polimerasa , Especificidad de la EspecieRESUMEN
In the present study, the intergenic region between the mitochondrial genes encoding subunit 3 of NADH dehydrogenase (nad3) and ribosomal protein S12 (rps12) was shown to contain a Gn mononucleotide microsatellite repeat. This region was analysed in 15 species belonging to the genus Pinus and interspecific variation was detected in the form of repeat length polymorphism. Sequence analysis of a 576-bp region containing the microsatellite confirmed that the variability was due to expansion and contraction of the repeat motif and that no point mutations were present in the coding regions of the two genes. This is the first report of the occurrence of a microsatellite polymorphism in plant mitochondria.
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Repeticiones de Microsatélite , Mitocondrias/genética , Árboles/genética , Secuencia de Bases , Cartilla de ADN , Genes de Plantas , Variación Genética , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido NucleicoRESUMEN
Moringa oleifera is an important multipurpose tree introduced to Africa from India at the turn of this century. Despite limited knowledge of the levels of genetic diversity and relatedness of introduced populations, their utilization as a source of seed for planting is widespread. In order to facilitate reasoned scientific decisions on its management and conservation and prepare for a selective breeding programme, genetic analysis of seven populations was performed using amplified fragment length polymorphism (AFLP) markers. The four pairs of AFLP primers (PstI/MseI) generated a total of 236 amplification products of which 157 (66.5%) were polymorphic between or within populations. Analysis of molecular variance (AMOVA) revealed significant differences between regions and populations, even though outcrossing perennial plants are expected to maintain most variation within populations. A phenetic tree illustrating relationships between populations suggested at least two sources of germplasm introductions of Kenya. The high levels of population differentiation detected suggest that provenance source is an important factor in the conservation and exploitation of M. oleifera genetic resources.
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We have used polymorphic chloroplast simple-sequence repeats to analyse levels of genetic variation within and between seven native Scottish and eight mainland European populations of Scots pine (Pinus sylvestris L.). Diversity levels for the Scottish populations based on haplotype frequency were far in excess of those previously obtained using monoterpenes and isozymes and confirmed lower levels of genetic variation within the derelict population at Glen Falloch. The diversity levels were higher than those reported in similar studies in other Pinus species. An analysis of molecular variance (AMOVA) showed that small (3.24-8.81%) but significant (p < or = 0.001) portions of the variation existed between the populations and that there was no significant difference between the Scottish and the mainland European populations. Evidence of population substructure was found in the Rannoch population, which exhibited two subgroups. Finally, one of the loci studied exhibited an allele distribution uncharacteristic of the stepwise mutation model of evolution of simple-sequence repeats, and sequencing of the PCR products revealed that this was due to a duplication rather than slippage in the repeat region. An examination of the distribution of this mutation suggests that it may have occurred fairly recently in the Wester Ross region or that it may be evidence of a refugial population.